d-Serine enhances fear extinction by increasing GluA2-containing AMPA receptor endocytosis

Abstract Activation of the N-methyl- d -aspartate receptor (NMDAR) glycine site has been shown to enhance memory extinction in physiological and pathological conditions. In the current study, we examined the effects of d -serine, an endogenous NMDAR glycine site agonist, on fear extinction and α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) endocytosis in the hippocampus during the process of fear extinction. In inhibitory avoidance task, systemic administration of d -serine (800 mg/kg, i.p.) significantly accelerated memory extinction. The Western blot analyses showed that the acceleration of memory extinction was accompanied by an increase in postsynaptic AMPAR endocytosis in the hippocampus. Furthermore, the application of a synthetic peptide Tat-GluA2 3Y (3.0 μmol/kg, i.p.) that interferes with the endocytosis of AMPARs succeeded in preventing the enhancement of fear extinction and AMPAR endocytosis induced by d -serine. These results suggest that d -serine might enhance fear extinction through increasing GluA2-containing AMPA receptor endocytosis, and that d -serine may be a potential therapeutic agent against learning and memory disorders.